Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein secreted by macrophages, fibroblasts, and endothelial cells originally identified by its ability to stimulate the survival, proliferation, and differentiation in vitro of predominantly neutrophilic granulocytes from bone marrow progenitors. Nicola, N. A., Annu. Rev. Biochem. (1989) 58:45. The capacity of G-CSF to regulate in vivo granulopoiesis is supported by animal and clinical studies, which demonstrated a reversible rise in circulating neutrophil levels in response to administered recombinant G-CSF. Gabrilove, J. L. et al., N. Engl. J. Med. (1988) 318:1414. G-CSF has pleiotropic effects on mature neutrophils, enhancing their survival and stimulating functional activation, including induction of neutrophil alkaline phosphatase (Sato. N. et al., J. Cell. Physiol. (1988) 37:272) and high affinity IgA F.sub.c receptors (Weisbart, R. H., et al., Nature (Lond.) (1988) 332:647), priming for respiratory burst (Nathan, C. F. Blood (1989) 73:301) and increased chemotaxis (Wang, J. M., Blood (1988) 72:1456). G-CSF effects have also been observed on hematopoietic cells that are not committed to the granulocyte lineage, for example, stimulation of the proliferation on monocytic differentiation in vitro of some myeloid leukemic cells (Geissler, K., J. Immunol. (1989) 143:140) and the proliferation in vitro of some multipotential hematopoietic precursors (Ferrero, D., Blood (1989) 73:402).
Administration of recombinant G-CSF to patients suffering from neutropenia due to various causes indicated that G-CSF is beneficial as an adjuvant in chemotherapy and in bone marrow transplantation (Morstyn, G., et al., Trends Phannacol. Sci. 10, (1989) 154-159). G-CSF activity is also associated with mobilization of hematopoietic stem cells from the marrow to the peripheral blood. (See review article, Good Review article Haylock et al., Blood 89:2233-2258, 1997).
It would be desirable to provide compounds which allow for the treatment of neutropenia to enhance leukocyte production by acting as a G-CSF mimetic.
As disclosed herein it has unexpectedly been discovered that certain non-peptide compounds are effective as G-CSF minmetics.
As disclosed herein it has unexpectedly been discovered that certain selected 2,5-Diimino-3a,6a-diaryl-1,2,3,3a,4,5,6,6a-octahydroimidazo[4,5-d]imidazol es are effective as G-CSF mimetics.